The secretion of gonadotropin-releasing hormone (GnRH) is critical for regulating the pituitary-gonadal axis and ensuring reproductive competence for virtually all vertebrates. GnRH neurons migrate from the olfactory placode across the cribriform plate and olfactory bulb, into the forebrain and hypothalamus during embryonic and early postnatal development. The majority of GnRH neurons migrate along the VNN through the nasal cavity. GnRH neurons then leave the main VNN and follow a small group of axons directly into the brain. We have recently identified the migratory track as a subset of the vomeronasal nerve. Preliminary studies suggest that 3 events play a role in the regulation of GnRH migration: i) GnRH neurons interact specifically with ligands on the migratory pathway; and ii) a group of co-migrating GABAergic neurons modulates the migration of GnRH neurons , and iii) selective axon branching and guidance of the caudal VNN establishes a chemically unique track for GnRH neurons. Our objective is to determine the molecular basis of directed GnRH neuron migration. Perturbation studies with enzymes, peptides, ligands, proteins and antibodies using in vitro slice cultures of the nose and forebrain, and in vivo will define the factors that regulate movement along the known route of GnRH cell migration. We will develop an in vivo marker for GnRH neurons in transgenic mice using transgenes containing the human GnRH promoter fused to green fluorescent protein cDNA. Green fluorescent protein (GFP)containing transgenic GnRH cells fluoresce when exposed to 395- 470nm light, and are thus identifiable microscopically in living tissue. GFP transgenic mice, in conjunction with slice cultures will allow us to test hypotheses that GnRH neurons use caudal branches of the VNN as guides for migration into the forebrain. The developmental relationship of the olfactory system and the forebrain is clinically significant. X-linked Kallmann syndrome is caused by a defect in the development of the olfactory system. This syndrome is characterized primarily by the inability to smell, anosmia; and abnormal development of the gonads, hypogonadotrophic hypogonadism. it has also been associated with numerous other neurological problems, including mental retardation. Results from these studies will aid our understanding of the development of the nervous system.